Genetic study of epilepsies and febrile convulsions

本报告总结了我们在不同癫痫表型基因中发现的新突变，以及突变基因功能分析的主要结果。作为良性家族性新生儿惊厥(BFNC)的原因，我们鉴定了KCNQ2和KCNQ3的突变。BFNC的年龄依赖性发育和自发缓解的发病机制与新生CNS中抑制性KCNQ通道活性的增龄性降低和GABA能系统从兴奋性到抑制性的增龄性功能转换的相互作用有关。与常染色体显性遗传性额叶癫痫相关的神经型烟碱型乙酰胆碱受体α4亚单位突变(Ser284Leu)导致大鼠卵母细胞表达的受体快速脱敏。我们在JME家系中发现了位于染色体6p12-p11上的一个新基因，并在舞蹈性棘细胞增多症患者中发现了一个以前未知的全长编码结构蛋白的基因，我们将其命名为Chorein。我们报告了常染色体显性遗传性癫痫伴高热惊厥和婴儿期严重肌阵挛癫痫与钠通道亚单位(SCN1A，SCN1a)基因的各种突变有关拉福林(一种主要与多聚核糖体相关的细胞质蛋白)是一种由γ基因缺陷编码的双特异性磷酸酶。EPM2A基因外显子1突变与早发性认知障碍亚型有关。目前，癫痫常见表型的基因已被发现，但毫无疑问，这些基因很快就会被发现。

This report summarizes our own discoveries of novel mutations in the genes of various epilepsy phenotypes, and of the main results of functional analyses of the mutated genes.As a cause of benign familial neonatal convulsions (BFNC), we identified mutations of KCNQ2 and KCNQ3. The pathogenic mechanisms of age-dependent development and spontaneous remission of BFNC are associated with the interaction between age-dependent reduction of inhibitory KCNQ-channel activity and age-dependent functional switching of GABAergic-system from excitatory to inhibitory action in neonatal CNS. A mutation (Ser284Leu) of neuronal nicotinic acetylcholine receptor α4 subunit associated with autosomal dominant nocturnal frontal lobe epilepsy caused faster desensitization of rat receptor expressed in oocytes.We identified a novel gene in the EJM1 region on chromosome 6p12-p11 in families with JME (in contribution), and also identified a previously unknown, full-length of cDNA encoding a presumably structural protein, which we named chorein, in patients with chorea-acanthocytosis.We reported that autosomal dominant epilepsy with febrile seizure plus and severe myoclonic epilepsy of infancy were associated with various mutations of genes encoding both Na^+ channel subunit (SCN1A, SCN2A) and γ2-subunit of the GABA-A receptor (GABRG2).Laforin (a cytoplasmic protein associated primarily with polyribosome) is a dual-specificity phosphatase coded by the EPM2A gene defective in Lafora's disease. Exon 1 mutations of EPM2A was associated with an early-onset cognitive deficit subphenotype.Genes responsible for common phenotypes of epilepsy have been uncovered yet, however, these will undoubtedly be discovered soon.